Dev. Cell https://doi.org/10.1016/j.devcel.2019.01.001 (2019)

Adult zebrafish hearts undergo vigorous regeneration upon injury through dedifferentiation and proliferation of cardiomyocytes. Though cyclin-dependent kinases and ErbB2 have been identified as regulators of cardiomyocyte proliferation, large-scale genetic identification of related mediators has remained difficult. Han et al. used a fluorescent ubiquitin-based cell cycle indicator to identify compounds that increase cardiac proliferation in embryonic zebrafish. Vitamin D analogs were identified as promoters of embryonic and adult cardiomyocyte proliferation and enhanced injury-induced regeneration, acting locally through cardiac vitamin D receptors. Interestingly, injection of alfacalcidol also increased proliferation in other noncardiac tissues such as retinal cells and hepatocytes, suggesting that vitamin D may be a general regulator of cell division. Loss of vitamin D signaling through generation of vitamin D receptor mutants resulted in decreased length and lack of a proliferative response to alfacalcidol treatment. Finally, RNA-sequencing analysis revealed the ErbB2 signaling pathway as a downstream effector of vitamin D, and pharmacological ErbB2 inhibition blocked effects of alfacalcidol. Overall, these findings reveal a new mediator of organ growth and proliferation.